Inhibition of inducible nitric oxide synthase ameliorates endotoxin-induced gut mucosal barrier dysfunction in rats
Inhibition of inducible nitric oxide synthase ameliorates endotoxin-induced gut mucosal barrier dysfunction in rats
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DOI：
10.1053/gast.1997.v113.pm9322519
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发表时间：
1997-10-01
期刊：
影响因子：
29.4
通讯作者：
Fink, MP
中科院分区：
文献类型：
--
作者：
Unno, N;Wang, HL;Fink, MP
背景与目的：暴露于一氧化氮后，肠上皮单层的通透性增加。方法：大鼠注射生理盐水或IFS (5 mg/kg)，在LPS注射24小时后观察细菌在肠系膜淋巴结、肝脏和脾脏的易位，通过将荧光素标记的葡聚糖（mel wt， 4000道尔顿）加载肠段并测量其在血浆中的外观来测定粘膜通透性。采用3-（4,5-二甲基噻唑-2-基）-2,5-二苯基溴化四唑评估肠黏膜线粒体呼吸作用。结果;lps刺激大鼠肠组织中诱导型NO合成酶（iNOS）信使RNA表达上调，iNOS酶活性随之上调。注射LPS后至少24小时，血浆中亚硝酸盐和硝酸盐（NO2-/NO3-）浓度升高。选择性iNOS抑制剂氨基胍抑制了iNOS酶活性和NO2-/NO3-的过量产生，氨基胍减少了lps诱导的细菌易位。氨基胍和另一种选择性iNOS抑制剂s -甲基异硫脲均可改善lps诱导的肠道高通透性。LPS抑制肠黏膜线粒体功能，氨基胍可改善这一作用。结论：LPS刺激大鼠体内一氧化氮的过量产生可能通过干扰线粒体氧化代谢而导致肠屏障功能障碍。
Background & Aims: The permeability of intestinal epithelial monolayers increases after exposure to nitric oxide. The aim of this study was to investigate the role of excessive NO production on intestinal barrier function in rats injected with lipopolysaccharide (LPS), Methods: Rats were injected with saline or IFS (5 mg/kg), Bacterial translocation to mesenteric lymph nodes, liver, and spleen was assessed 24 hours after LPS injection, Mucosal permeability was determined by loading fluorescein-labeled dextran (mel wt, 4000 daltons) into an intestinal segment and measuring its appearance in plasma. intestinal mucosal mitochondrial respiration was assessed using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide. Results; intestinal tissue from LPS-challenged rats showed upregulation of inducible NO synthase (iNOS) messenger RNA expression and subsequent up-regulation of iNOS enzymatic activity. Plasma concentrations of nitrite plus nitrate (NO2-/NO3-) were increased for at least 24 hours after injection of LPS. Treatment with the selective iNOS inhibitor, aminoguanidine, inhibited iNOS enzymatic activity and overproduction of NO2-/NO3-, LPS-induced bacterial translocation was reduced by aminoguanidine. LPS-induced intestinal hyperpermeability was ameliorated by both aminoguanidine and another selective iNOS inhibitor, S-methylisothiourea. LPS depressed intestinal mucosal mitochondrial function, and this effect was ameliorated by aminoguanidine, Conclusions: Overproduction of NO may contribute to intestinal barrier dysfunction in LPS challenged rats, possibly by Interfering with mitochondrial oxidative metabolism.